The vertebrate renal proximal tubule is responsible for the excretory transport of a large number of potentially toxic chemicals, including, waste products of normal metabolism, drugs, environmental pollutants and drug and pollutant metabolites. These chemicals are handled by multiple specific, transport proteins that remove them from the blood and concentrate them in urine. Our research focus is understanding control of these transporters. We use comparative models (intact proximal tubules from teleost fish and mammalian renal slices and cells in culture) in combination with confocal microscopy to identify the physiologically relevant extracellular signals (hormones, metabolites, xenobiotics), and the intracellular signaling pathways that modulate xenobiotic excretion in proximal tubule. Our experiments show separate mechanisms for short-term and long-term regulation of transport. In the short-term, all xenobiotic transport systems in proximal tubule are under control of hormones acting through protein kinase C (PKC). For example, endothelin (ET), acting through a basolateral, B-type ET receptor, a G-protein and PKC, rapidly (minutes) reduces transport mediated by the luminal ATP-driven xenobiotic export pumps, p-glycoprotein and Mrp2, while parathyroid hormone (PTH) acting through a basolateral receptor and PKC rapidly reduces organic anion transport mediated by the basolateral transporters Oat1/3. Recent experiments indicate that 1) nitric oxide is generated after ET binds to its receptor but before PKC activation, and 2) three structurally unrelated classes of nephrotoxicants (radiocontrast agents, aminoglycoside antibiotics and heavy metal salts) release ET from the tubules and thus fire the ET B-receptor-NO-PKC signaling pathway. This appears to be an early, common event in nephrotoxicant action which provides a possible link between ET-signaling and nephrotoxicity. Finally, over the longer-term, (hours to days) low concentrations of heavy metals, such as, Zn and Cd, upregulate transport mediated by Mrp2 and increase the Mrp2 content of the tubules.